By Jenny C Leary

Since it started more than 30 years ago, funding the graduate medical education (GME) system has not evolved even as there has been a revolution in GME. The United States contributes almost $10 billion a year from Medicare into funding the GME system. However this system fails to provide the workforce needed for the 21st century and lacks the necessary transparency and accountability.

With an aging population and millions of people newly registered for health insurance because of the Affordable Care Act, there is a pressing need to increase the number of primary care physicians. In the United States, it is estimated that only 20.9 percent of residents graduating from GME programs will practice primary care.

Recommendations recently published in the Journal of General Internal Medicine prepared by the Health Policy Education Subcommittee of the Society of General Internal Medicine (SGIM) outline how to reform the GME system to support the development of a physician workforce that can provide high quality, high value, population-based, and patient-centered health care, aligned with the dynamic needs of America’s healthcare delivery system.

Dr. Angela Jackson

Angela Jackson, MD, associate dean for student affairs at Boston University School of Medicine and a physician in general internal medicine at Boston Medical Center, is the article’s first author and is Co-Chair of the SGIM’s Health Policy Committee.

“SGIM hopes its policy and paper will invigorate the debate on GME funding, moving beyond discussions limited to funding levels to discussions on GME program accountability for public fund use and how to shape a GME system that will provide the nation with the physician workforce that we need,” said the authors.

A team of Boston University School of Medicine (BUSM) researchers have proposed that an “on and off” epigenetic switch could be a common mechanism behind the development of different types of cancer. Epigenetics is the phenomena whereby genetically identical cells express their genes differently, resulting in different physical traits.Researchers from the Boston University Cancer Center recently published two articles about this in Anticancer Research and Epigenomics.

The current paradigm states that cancer develops from environmental and genetic changes to cancer progenitor cells. These changes are the result of mutations, exposure to toxic substances or hormonal imbalances.

Cancer progression is extremely complex, however. It also is well known that new mutations and the activation of more cancer causing genes occur throughout the development and progression of cancer.

“If we believe that everything in nature occurs in an organized fashion, then it is logical to assume that cancer development cannot be as disorganized as it may seem,” said Sibaji Sarkar, PhD, instructor of medicine at BUSM and the articles corresponding author. “There should be a general mechanism that initiates cancer progression from predisposed progenitor cells, which likely involves epigenetic changes.”

The existence of this epigenetic switch is indirectly supported by the fact that tumors develop through different stages. When cells rapidly grow during cancer progression, they become stuck in their current stage of development and their cell characteristics do not change. This is the reason that there are so many types of leukemia—the characteristics that a leukemia cell possesses when it begins to rapidly grow and expand are the characteristics that it will keep until the rapid growth stops.

“If we believe that all of the irreversible changes, mutations and effects of carcinogens make cells rapidly grow, then the mechanism that allows cells to stop growing and assume new changes in character must be of great importance,” added Sarkar. “The study of cancer progression is key to understanding how cancer cells continue to differentiate.”During cancer progression, there are different stages of rapid growth and differentiation. The control that allows for this switch between growth and differentiation can only be achieved through reversible mechanisms, such as epigenetic changes.

Sarkar and colleagues have previously proposed that epigenetic changes are involved in cancer progenitor cell formation and cancer progression. They also believe that epigenetic changes have the ability to control rapid growth and change of characteristics (different grades/types of tumors).

Sarkar compares the stages of cancer growth to a rocket orbiting in space – that is, that an object within an orbit continues to circle a given path, until it is given a signal (or additional fuel) to propel itself into a further orbit. This comparison can be made for cancer progenitor cells and epigenetics. A specific cell continues to grow at a certain stage until it is given a signal – in this case, an epigenetic switch – that propels it to differentiate into a new orbit, or further differentiated cell.

Shannon Byler

“While the specific details of the epigenetic code that regulates these changes has not been discovered, the fact that we have a possible explanation for the reversible and ever-changing characteristics for cancer progenitor cells is very exciting,” said Sarkar. “Future epigenetics findings hold the key to develop drugs which could possibly kill cancer progenitor cells to reduce cancer relapse and drug-resistant cancer cells.”

Shannon Byler, who served as the first author for both articles, is a student at Boston University. Other BU student co-authors of the Anticancer Research article are Sarah Goldgar, Sarah Heerboth, Meghan Leary, Genevieve Housman and Kimberly Moulton.

Physicians from Boston University School of Medicine (BUSM) and Boston Medical Center (BMC) have helped create the first set of clinical guidelines for treating patients with pulmonary hypertension in sickle cell disease. Elizabeth Klings, MD, director of the pulmonary hypertension inpatient and education program at BMC and associate professor of medicine at BUSM, spearheaded the development of these guidelines, which are published in the American Journal of Respiratory and Critical Care Medicine.

Several studies conducted in the past decade have demonstrated that cardiopulmonary complications, including pulmonary hypertension, are primary risk factors for death in patients with sickle cell disease (SCD). Pulmonary hypertension (PH) affects between six and 11 percent of adults with SCD and is an independent risk factor for death in these patients. This complication is often under-recognized and many patients are not diagnosed early in the course of their disease.

A group of 24 national physician leaders in pediatric and adult hematology, pulmonology and cardiology convened to develop guidelines specific to these patients. Funded by the American Thoracic Society and endorsed by the Pulmonary Hypertension Association and the American College of Chest Physicians, these guidelines represent the most comprehensive pulmonary recommendations thus far.

“I am proud to have collaborated with my colleagues across disciplines to create these guidelines, which will help providers recognize the link between sickle cell disease and pulmonary hypertension and deliver the optimum care to these patients,” said Klings.

Some of the guidelines include screening SCD adults for pulmonary hypertension even if they are asymptomatic every one to three years. All SCD patients with symptoms suggestive of PH, such as exertional shortness of breath and chest pain, should undergo a full PH workup. These patients are often best managed in a specialty center with expertise in the management of PH and SCD. The guidelines also recommend intensifying SCD therapy for all patients with pulmonary hypertension or an elevated pulmonary artery systolic pressure by echocardiography as these patients are also at an increased risk for death. The management of pulmonary hypertension in these patients is dictated by the hemodynamic numbers obtained by a catheterization of the pulmonary arteries. Patients with symptomatic PH should be considered for treatment of their condition.

Klings sees patients in the Boston University Center of Excellence in Sickle Cell Disease as well as in the Pulmonary Clinic at BMC. The Center also promotes interactive basic and clinical research and patient and professional educational activities. For more information, visit http://www.bu.edu/sicklecell/.

A recent study from Boston University School of Medicine (BUSM) and Boston Medical Center (BMC) shows a significant decrease in severe sepsis mortality rates over the past 20 years. Looking at data from patients with severe sepsis enrolled in clinical trials, researchers found that in-hospital mortality rates decreased from 47 percent between 1991 and 1995 to 29 percent between 2006 and 2009, a time period when no new pharmacological treatments were developed for severe sepsis. The results suggest that substantial improvements in patient outcomes can be accomplished by improving processes of care and working with existing treatments in a novel way.

The study, which is published online in Critical Care Medicine, was led by senior author Allan J. Walkey, MD, MSc, assistant professor of medicine, BUSM, and attending physician, pulmonary, critical care and allergy medicine, BMC.

Severe sepsis, which affects approximately one million Americans each year, occurs when a local infection causes other organs in the body to fail. For example, a patient with severe sepsis could have an infection that starts as pneumonia, but a counterproductive immune response results in damage to distant organs, such as new onset kidney failure, altered mental status and/or dangerously low blood pressure (shock). It can be imminently life threatening – approximately one out of three patients die from severe sepsis during their hospitalization.

Because prior studies suggesting a decrease in severe sepsis mortality rates used only billing codes from administrative data, it was thought that billing code changes may be responsible for the mortality decline. To avoid administrative data issues and determine trends in patients prospectively identified as having severe sepsis, this study looked at data from patients with severe sepsis enrolled in 36 multicenter clinical trials from 1991-2009.

The results showed that despite no change over time in the severity of illness of the patients with severe sepsis enrolled in the clinical trials, mortality rates declined significantly over 20 years, and the decline occurred without the development of new pharmacological therapies targeted to treat severe sepsis.

Previous studies have suggested that having more critical care physicians providing care, earlier initiation of antibiotics, more targeted delivery of intravenous fluids and more gentle mechanical ventilation may improve outcomes of patients with severe sepsis. However, whether findings from these past studies were implemented into routine practice and were associated with improved severe sepsis patient outcomes in the real world was previously unclear.

“Even without new drugs or technologies to treat severe sepsis, our study suggests that improving the ways in which we recognize and deliver care to patients with severe sepsis could decrease mortality rates by a magnitude similar to new effective drug,” said Walkey.

Additional studies are needed to determine what specific changes in care have had the most impact on decreasing the mortality rates of patients with severe sepsis.

This study was funded in part by the National Institutes of Health’s National Heart, Lung, and Blood Institute under grant award number K01HL116768.

Researchers at Boston University School of Medicine (BUSM) have uncovered important clues about a biochemical pathway in the brain that may one day expand treatment options for schizophrenia. The study, published online in the journal Molecular Pharmacology, was led by faculty within the department of pharmacology and experimental therapeutics at BUSM.

Patients with schizophrenia suffer from a life-long condition that can produce delusions, disordered thinking, and breaks with reality. A number of treatments are available for schizophrenia, but many patients do not respond to these therapies or experience side effects that limit their use.

This research focused on key components of the brain known as NMDA receptors. These receptors are located on nerve cells in the brain and serve as biochemical gates that allow calcium ions (electrical charges) to enter the cell when a neurotransmitter, such as glutamate, binds to the receptor. Proper activation of these receptors is critical for sensory perception, memory and learning, including the transfer of short-term memory into long-term storage. Patients with schizophrenia have poorly functioning or “hypoactive” NMDA receptors, suggesting the possibility of treatment with drugs that positively affect these receptors. Currently the only way to enhance NMDA receptor function is through the use of agents called agonists that directly bind to the receptor on the outer surface of the cell, opening the gates to calcium ions outside the cell.

In this study, the researchers discovered a novel “non-canonical” pathway in which NMDA receptors residing inside the cell are stimulated by a neuroactive steroid to migrate to the cell surface (a process known as trafficking), thus increasing the number of receptors available for glutamate activation. The researchers treated neural cells from the cerebral cortex with the novel steroid pregnenolone sulfate (PregS) and found that the number of working NMDA receptors on the cell surface increased by 60 to 100 percent within 10 minutes. The exact mechanism by which this occurs is not completely clear, but it appears that PregS increases calcium ions within the cell, which in turn produces a green light signal for more frequent trafficking of NMDA receptors to the cell surface.

Although still in the early stages, further research in this area may be instrumental in the development of treatments not only for schizophrenia, but also for other conditions associated with malfunctioning NMDA receptors, such as age-related decreases in memory and learning ability.

Finding could reduce need for blood donations, speed up research on therapies to treat diseases

Red Blood Cells and Platelets. Image courtesy of S. Kaulitzki.

A study led by Boston University School of Medicine has identified a novel approach to create an unlimited number of human red blood cells and platelets in vitro. In collaboration with Boston University School of Public Health (BUSPH) and Boston Medical Center (BMC), the researchers differentiated induced pluripotent stem (iPS) cells into these cell types, which are typically obtained through blood donations. This finding could potentially reduce the need for blood donations to treat patients requiring blood transfusions and could help researchers examine novel therapeutic targets to treat a variety of diseases, including sickle cell disease.

Published online in the journal Blood, the study was led by George J. Murphy, PhD, assistant professor of medicine at BUSM and co-director of the Center for Regenerative Medicine (CReM) at Boston University and BMC and performed in collaboration with David Sherr, PhD, a professor in environmental health at BUSM and BUSPH.

iPS cells are derived by reprogramming adult cells into a primitive stem cell state that are capable of differentiating into different types of cells. iPS cells can be generated from mature somatic cells, such as skin or blood cells, allowing for the development of patient-specific cells and tissues that should not elicit inappropriate immune responses, making them a powerful tool for biological research and a resource for regenerative medicine.

In this study, the iPS cells were obtained from the CReM iPS Cell Bank. The cells were exposed to growth factors in order to coax them to differentiate into red blood cells and platelets using a patented technology. These stem cells were examined in depth to study how blood cells form in order to further the understanding of how this process is regulated in the body.

In their new approach, the team added compounds that modulate the aryl hydrocarbon receptor (AhR) pathway. Previous research has shown this pathway to be involved in the promotion of cancer cell development via its interactions with environmental toxins. In this study, however, the team noted an exponential increase in the production of functional red blood cells and platelets in a short period of time, suggesting that AhR plays an important role in normal blood cell development.

“This finding has enabled us to overcome a major hurdle in terms of being able to produce enough of these cells to have a potential therapeutic impact both in the lab and, down the line, in patients,” said Murphy. “Additionally, our work suggests that AhR has a very important biological function in how blood cells form in the body.”

Blood transfusion is an indispensable cell therapy and the safety and adequacy of the blood supply is an international concern. In 2009, the National Blood Data Resource Center reported that blood-banking institutions collected more than 17 million units of whole blood and red blood cells and US hospitals were transfusing more than 15 million patients annually. Given the variety of blood types, there are – even in developed countries – chronic shortages of blood for some groups of patients. Sporadic shortages of blood also can occur in association with natural or man-made disasters. The number of blood transfusions is expected to increase in people over the age of 60 and could lead to an insufficient blood supply by 2050.

“Patient-specific red blood cells and platelets derived from iPS cells, which would solve problems related to immunogenicity and contamination, could potentially be used therapeutically and decrease the anticipated shortage and the need for blood donations,” added Murphy.

iPS-derived cells have great potential to lead to a variety of novel treatments for diseases given that they can be used to construct disease models in a lab. The iPS-derived red blood cells could be used by researchers examining malaria and sickle cell anemia while the iPS-derived platelets could be used to explore cardiovascular disease and treatments for blood clotting disorders.

Funding for this study was provided in part by the National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute (NHLBI) under grant award number U01 HL107443-01; a Scholar Award from the American Society of Hematology; an Affinity Research Collaborative award from the Evans Center for Interdisciplinary Research at BU; a training grant from the NIH’s NLHBI under award number 5T32HL007501-30; the NIH’s National Institute of Environmental Health Sciences under grant award numbers P01-ES11624 and P42ES007381; and the Art beCAUSE Breast Cancer Foundation.

To view an abstract of the study, visit http://bloodjournal.hematologylibrary.org/content/early/2013/05/29/blood-2012-11-466722.abstract.

Physicians from the Departments of Pediatrics and Family Medicine at Boston Medical Center (BMC) and Boston University School of Medicine (BUSM) are proposing that current pediatric guidelines and practices could be implemented within a Patient Centered Medical Home model to address social determinants of health. The article, published in the Journal of the American Medical Association (JAMA), also suggests that these guidelines could reduce socioeconomic disparities in health care for all patients.

Arvin Garg, MD, MPH, assistant professor of pediatrics at BUSM and pediatrician at BMC, served as the study’s first author. Barry Zuckerman, MD, professor of pediatrics at BUSM and a pediatrician at BMC, and Brian Jack, MD, Chief and Chair of Family Medicine at BMC and BUSM, were the article’s co-authors.

A Patient Centered Medical Home (PCMH) is a comprehensive and coordinated health care model in which a team of providers coordinate all of the patient’s health needs, including management of chronic health conditions, visits to specialists, hospital admissions and routine health screenings. Socioeconomic disparities continue to play a role in the health of children and families. Previous studies have shown that the environment in which a patient lives can impact their health, and these factors have historically been managed by public health and community organizations. However, a PCMH model allows for physicians to play a role in examining the social determinants of health in order to assess and treat patients with a more holistic approach and improve population health.

The authors list five recommendations to help address social context of patient care within the PCMH model: making social determinants of health an important aspect of clinical guidelines; screening for particular social determinants at medical visits; helping patients and families access community based resources, such as Women, Infants, and Children (WIC), job training and food pantries; implementing “outside the box” multidisciplinary primary care interventions, such as programs like Reach out and Read, the Medical-Legal Partnership and Health Leads (developed at BMC); and integrating home visiting programs to better understand living conditions.

They suggest that the implementation of these guidelines will provide important data about the types of services necessary to improve population health. Additionally, the indicators related to social determinants of care may some day become part of pay for performance and quality evaluation metrics of the medical home model.

“Overall, implementing social determinants of health within the PCMH model will potentially reduce socioeconomic disparities in health that continue to exist today and ultimately improve the health care system, especially for PCMH’s that serve low-income patient populations,” said the authors.

The authors note that the “medical home” is not a novel concept in the world of pediatrics. Current guidelines and practices within pediatrics now address social risks of populations and these guidelines are adaptable to adult and elderly populations within the medical home as well.

Results of a pilot study suggest that a virtual patient advocate (VPA) could help influence positive changes and help women have healthier pregnancies. Developed at Boston University School of Medicine (BUSM), Boston Medical Center (BMC) and Northeastern University, “Gabby” (pictured below) is an innovative tool developed to deliver preconception care (PCC) to African-American women through interactive conversations online.

The study results, which are published online in the American Journal of Health Promotion, suggest that Gabby could help identify risk factors and influence positive changes in women before they conceive and decrease the risk for adverse birth outcomes. Paula Gardiner, MD, MPH, assistant professor at BUSM and family medicine physician at BMC, is the paper’s first author. Brian Jack, MD, chief and chair of family medicine at BMC and BUSM, respectively, is the paper’s senior author. Timothy Bickmore, PhD, associate professor in the College of Computer and Information Science at Northeastern, collaborated on this study and led the development of the software on which Gabby is based.

This is Gabby, a Virtual Patient Advocate developed for preconception care

PCC addresses family planning, medical conditions and preventive behaviors in a primary care setting. The Centers for Disease Control and Prevention (CDC) developed evidence-based best practice guidelines for PCC, but there is a need for more comprehensive PCC implementation. Statistics show that approximately half of pregnancies in the U.S. are unplanned. According to the CDC, the fetal mortality rate for non-Hispanic African-American women in 2005 was 2.3 times the rate for non-Hispanic white women.

“Because approximately half of pregnancies in the United States are unplanned, delivering preconception care during general wellness visits could help reduce infant and maternal mortality rates,” said Gardiner.

In order to develop a VPA that participants could identify with and trust, researchers conducted usability studies to gather recommendations from participants about the name, gender and physical appearance of the VPA. Previous research has shown that African-Americans prefer a VPA who is their same race and gender, and the results of these studies also indicated that participants would feel comfortable discussing PCC health topics with a VPA who was a young, female health care provider. These results helped the researchers create Gabby.

Women between the ages of 15 and 25 interact and engage with Gabby online by answering her questions about current health habits and conditions. Through this interactive dialogue, where participants can pick from answers or write in their own, Gabby screens for PCC risks, educates the participants about their risks and assesses whether they are ready to make lifestyle changes to decrease their risks. Based on participant’s responses, Gabby helps create a custom “My Health To-Do List,” which users can review and share with their providers.

Participants reported an average of 23 preconception risks. In the two-month pilot study, 83 percent of the risks added to the “My Health To-Do List” were either addressed or resolved by the users by the end of the pilot. For example, if a woman identified that she was not taking folic acid at the beginning of the pilot but had bought a folic acid supplement, she had addressed the risk. If she started taking it by the end of the pilot, she had resolved the risk. Therefore, Gabby was effective in helping those who were contemplating behavior change to move forward and take action.

The participants indicated that the Gabby system is a valuable addition to their health care routine and could be used either to prepare for an appointment with a provider or to reinforce information discussed during an appointment. They found Gabby trustworthy and reliable and found that she provided helpful information in an appropriate amount of time. The results also show that Gabby addressed some barriers to translating PCC best practices to clinical care, such as ease of delivery and patient acceptability.

“These results suggest that using Gabby as a PCC tool could be effective in helping deliver PCC to African-American women,” said Jack.

The researchers are working to expand on these results and have been recruiting for a randomized control trial to test whether participants who receive PCC with Gabby will have fewer preconception risk factors after six months than participants in a control group. They will enroll 100 young African-American women from across the country.

This research was supported by the Agency for Healthcare Research and Quality under contract number HHSA 290-06-00012-7 (Principal Investigator: Jack); the Bureau of Maternal and Child Health in the Health Resources and Services Administration under grant award # R40 MC21510-01 (Principal Investigator: Jack); and the National Institute of Health’s National Center for Complementary and Alternative Medicine under grant award # K07AT005463-01(Principal Investigator: Gardiner).

The Alpha-1 Project (TAP) announced a $150,000 commission to Darrell Kotton, MD, to expand development of induced pluripotent stem cell (iPSC) lines created from tissue donated by patients with Alpha-1 Antitrypsin Deficiency (Alpha-1). Kotton is Professor of Medicine and Co-director of both The Alpha-1 Center and the Center for Regenerative Medicine at Boston University School of Medicine and Boston Medical Center.

“We are happy to announce The Alpha-1 Project’s investment in providing tools for researchers and industry,” said Jean-Marc Quach, Executive Director of TAP. “This commission signals our intent to direct research and resources aimed at speeding the development of new therapies for Alpha-1. I must emphasize that additional funds will need to be raised from the community if Dr. Kotton is to meet the goal of completing 20 stem cell lines over the next three years.”

Kotton plans to make the Alpha-1 iPSC lines available to all researchers interested in studying stem cell technology and possible therapies for Alpha-1.

“We’re excited to expand our research resource portfolio for the international investigator community with the leading-edge technology of these cell lines,” said John Walsh, President and CEO of the Alpha-1 Foundation and member of TAP’s board of directors. “Dr. Kotton is a leader in Alpha-1 research and in sharing his findings with other researchers. He has created a best-in-class Clinical Resource Center and set an example of embracing our community by his participation in conferences and inviting Alphas to tour his lab, meet his colleagues, and participate in his clinical research. We’re committed to raising the additional funds to promote access to this incredible resource.”

The development of the stem cells is exciting in part because, unlike embryonic stem cells, they are created from cells donated by living adults with Alpha-1. Since iPSC cells are undifferentiated, they can be induced to grow into various organ cells.

Kotton is well known for championing “open source” biology, sharing his findings, cells, reagents, and ideas with other researchers. In 2012, he and Jayaraj Rajagopal, MD, at Massachusetts General Hospital and Harvard Stem Cell Institute, announced that their teams had collaborated to develop new ways to turn stem cells into different types of lung tissue, surmounting a major hurdle in trying to harness the power of stem cell biology to study and develop treatments for major lung diseases.

“We are grateful to The Alpha-1 Project for its support, and we hope that the Alpha-1 iPSC bank will serve as an international resource for all those dedicated to advancing Alpha-1 research,” said Kotton. “Each cell line represents an essentially inexhaustible source of tissues derived from a tiny donated blood or skin sample from 20 individuals with Alpha-1. These cells can be shipped to any investigator interested in modeling Alpha-1 liver and lung disease in their own laboratories. We hope that this type of community-wide effort will one day accomplish our shared mission of finding better treatments for this inherited disease.”

Kotton currently has three cell lines developed from patients, which he freely shares with the global academic research community. The 20 additional cell lines will represent many different Alpha-1 phenotypes and genotypes.

Kotton, together with his Boston University colleague, Andrew Wilson, MD, in 2011 founded The Alpha-1 Center, focused on complete care of patients with Alpha-1. The two colleagues also direct joint basic science laboratories with a history of advancing Alpha-1 related research.

The Alpha-1 specialists at BU’s Alpha-1 Center are among more than 70 Alpha-1 Foundation Clinical Resource Centers across North America.

About The Alpha-1 Project

Mission statement: The Alpha-1 Project will work with patients, academia, pharmaceutical and biotech companies, and public health organizations in the relentless pursuit of cures and therapies for COPD and liver disease caused by Alpha-1 Antitrypsin Deficiency. For more information, visit www.thealpha-1project.com. The Alpha-1 Project is a wholly-owned for-profit subsidiary of the Alpha-1 Foundation. For more information on the Foundation, visit www.alpha-1foundation.org.

BUSM researchers have pinpointed a genetic signature for chronic obstructive pulmonary disease (COPD) from airway cells harvested utilizing a minimally invasive procedure. The findings provide a novel way to study COPD and could lead to new treatments and ways to monitor patient’s response to those treatments. The study is published online in the American Journal of Respiratory and Critical Care Medicine.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that leads to the loss of lung function primarily caused by cigarette smoking. It causes coughing, wheezing, shortness of breath, chest tightness and other symptoms that make it difficult to breathe. While there are treatments and lifestyle changes that can help people cope with COPD, there currently is no cure and there are no effective therapies to reduce the rate of lung function decline. According to the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI), which partially funded the study, COPD is the third leading cause of death in the United States, resulting in approximately 135,000 deaths each year.

“There have been limited molecular studies of COPD given the inaccessibility and invasiveness of obtaining lung tissue,” said Katrina Steiling, MD, MSc, assistant professor of medicine at BUSM who served as the study’s first author. The researchers hypothesized that while COPD primarily affects the tissue deep within the lung, the effects of COPD might be detectable in relatively accessible tissue throughout the respiratory tract. This echoes previous work they had done that found that cancer found deep in the lung could be detected by cancer-specific patterns of gene expression in the largest airways connected to the windpipe, far from the tumor.

To examine their hypothesis, the research team used airway cells obtained during a bronchoscopy, a procedure that involves putting a small camera into the airway through the nose or mouth. During the procedure, which can be done while a patient is awake under local anesthesia or moderate sedation, a cytology brush is used to gently scrape the sides of airways to collect cells.

They examined 238 samples from current and former smokers that had been collected by Stephen Lam, MD, a collaborator from the University of British Columbia. Eighty seven of the samples were from patients who had been diagnosed with mild to moderate COPD based on their lung function. The other 151 samples represented patients who did not have COPD based on these criteria.

When the researchers compared the airway samples from both groups, they found that 98 genes were expressed at different levels in those diagnosed with COPD compared to those without COPD. In order to determine how similar the airway cell changes were to lung tissue cells, the researchers compared their results with previously published findings on the gene expression changes associated with COPD in lung tissue. The results of the comparison demonstrate that the changes that occur in the airway cell samples in those diagnosed with COPD were similar to the changes in lung tissue cells of individuals with the disease despite the airway cells coming from regions of the lung not thought to be altered by disease.

“Our data shows that there are consistent gene-expression changes that occur in both airway and lung tissue cells in individuals with COPD,” said Avrum Spira, MD, MSc, Alexander Graham Bell professor of medicine and chief of the division of computational biomedicine at BUSM who served as one of the senior co-authors of the study. Spira also is a physician in the pulmonary, critical care and allergy department at Boston Medical Center.

To investigate the effects of treatment on the COPD-associated gene expression changes, the researchers collaborated with a team led by Maarten van den Berge, MD, PhD, from the University of Groningen Medical Center in the Netherlands that had collected airway cells from COPD patients before and after they started steroid therapy. They found that the expression of some genes that changed due to COPD reversed their expression after treatment and started to look more like the levels seen in current or former smokers without COPD.

“Part of the COPD ‘signature’ reverses with therapy, suggesting that examining airway cells might be a minimally invasive tool for monitoring the disease and evaluating the response to therapy more quickly in order to determine the best course of treatment for each individual patient,” said Marc Lenburg, PhD, associate professor in computational biomedicine and bioinformatics at BUSM and the study’s other senior co-author.

“Studying COPD using the large airway opens up some really exciting new avenues of research that could also improve care for patients with COPD,” said Spira. “While we are still at an early stage, I envision being able to examine airway cells from my patients with COPD to determine what is causing the disease and, from that information, recommend a more specific and effective treatment.”

Funding for this research was provided in part by the National Institutes of Health’s (NIH) NHLBI under grant award number 1R01 HL095388 (PI: Spira/Lenburg) and the NIH’s National Center for Advancing Translational Science through the Boston University Clinical and Translational Science Institute under award number KL2RR025770.